This project will provide new understanding of how mesenchymal populations can contribute to the maintenance of a tissue critical for host defense, the hematopoietic system. The proposed aims will inform us about the dynamics of a support population or 'stroma'that is often regarded as a merely supportive architecture for the work of the parenchymal cells that carry out the work of a given organ or tissue. Here will use the tractable system of hematopoiesis to examine the mesenchymal-parenchymal interactions in detail and define whether mesenchymal cells should be considered more broadly in the context of tissue dysfunction and disease. Further, we will learn the molecular basis for at least one variant of a condition of high morbidity, myelodysplasia. Determining whether similar pathways participate in the myelodysplasia of HIV infection may be possible in the out years of the grant, but is considered only feasible if the groundwork detailed here is conducted. PUBLIC HEALTH RELEVANCE: This proposal focuses on defining how the structural components of the bone marrow contribute to the healthy and diseased function of the hematopoietic or blood forming stem cells. It is intended to provide novel opportunities for intervening to overcome defects in blood formation associated with myelodysplasia.